Process for the cyclization of aryl(methylsulfinyl)-methyl ketones and compounds produced thereby

ABSTRACT

The invention relates to novel compounds having the formulas I and III:   wherein, in formula I, X is 43 O- or -N-COR wherein R is lower alkyl or aryl, and Z is   WHEREIN R&#39;&#39; is hydrogen, halogen or alkoxy. The compounds of this invention are prepared by a novel process which involves the cyclization of the corresponding aryl(methylsulfinyl)methyl ketones. The compounds of this invention having formulas I and III are useful in the treatment of hyperacidity and for alleviating allergic manifestations.

United States Patent [19] Connor et al.

[4 Nov. 18, 1975 PROCESS FOR THE CYCLIZATION OF ARYL(METHYLSULFlNYL)-METHYL KETONES AND COMPOUNDS PRODUCED THEREBY [75] Inventors: David T. Connor, Parsippany; Maximilian von Strandtmann, Rockaway, both of NJ.

[73] Assignee: Warner-Lambert Company, Morris Plains, N.J.'

[22] Filed: Apr. 26, 1974 121 App]. No.: 464,706

[56] References Cited UNITED STATES PATENTS 3,256,301 6/1966 Oftedahl 260/346.2

Primary Examinerl-larry l. Moatz Attorney, Agent, or Firm-Albert H. Graddis; Frank S. Chow; Anne M. Kelly [57] ABSTRACT The invention relates to novel compounds having the formulas l and ill:

SCH

SCH

, I III wherein, in formula I, X is 43 O- or NCOR wherein R is lower alkyl or aryl, and Z is v wherein R is hydrogen, halogen or alkoxy. The compounds of this invention are prepared by a novel process which involves the cyclization of the corresponding aryl(methylsulfinyl)methyl ketones. The compounds of this invention having formulas l and III are useful in the treatment of hyperacidity and for alleviating allergic manifestations.

8 Claims, No Drawings PROCESS FOR THE CYCLIZATION OF DESCRIPTION OF THE INVENTIONv The present invention relates'to novel substituted-2- (methylthio)-3(2I-I )-benzofuranones and novel substituted-Z-(methylthio)-3-indolinones having the formula I:

SCH

wherein X is .O or N COR wherein R is lower alkyl or aryl, and Z is wherein R is hydrogen, halogen or alkoxy; and to III This invention also includes within its scope a novel process for preparing the above compounds as well as certain novel intermediates used in their preparation.

The novel compounds of the invention having formula I, as defined above, are prepared by cyclizing the corresponding aryl-( methylsulfinyl)methyl ketone having the formula II:

i s-cH wherein X is O or NCOR wherein R is lower alkyl or aryl, and Z is MQK oer wherein R is hydrogen, halogen or alkoxy.

This cyclization reaction involves refluxing the keto sulfoxide starting material II with an equivalent of trifluoroacetic acid in a suitable solvent, such as benzene,

toluene or the like, for one to two hours. I The starting materials having the formula II as de- 1 scribed above wherein X is oxygen are prepared as de-,

scribed in US. Pat. No. 3,80l,644, patented Apr. 2,

1974: dimethyl sulfoxide is reacted with sodium hy dride in an inert solvent to which is added an appropriately. substituted ortho-hydroxy aromatic ester; the temperature is maintained at not more than 50C and the reaction product is precipitated by the addition of a. nonpolar solvent. Substituted.o-hydroxy-w-(methylsulfinyl)acetophenones or substituted o-hydroxy-m-(me thylsulfinyl)acetonaphthones used as starting materials for certain of the compounds of this invention are obtained by this method. For example, 2-hydroxy-2-( methylsulfinyl)-acetophenone; 2'-hydroxy-3'-methoxy-2-v (methylsulfinyl)acetophenone; 5-chloro-2-hydroxy- 2-(rnethylsulfinyI)acetophenone; 3'-hydroxy-2-(methylsulfinyl)2'-acetonaphthone may be prepared by this method. 7

Starting materials having the formula II wherein X is NCOR, with R representing lower alkyl or aryl, are prepared as described in M. von Stradtmannet al., Journal Organic Chemistryf36: 1742-1744 (1971) by the addition of sodium methylsulfinylmethide to the appropriately 3-substituted-2,4-benzoxazin- 1 one, to obtain such compounds as 2[(methylsulfinyl)acetyllbenzanilide; 2'[( rnethylsulfinyl)acetyllnaphthylbenzamidef 2'[ (methylsulfinyl)acetyl]loweralkyl-benia 'mide, and the like. i

Similarly, novel compounds of the invention having the formula III:

III

5 are IV:

4 I. OH CiOCIH SCH dissolved in a suitable solvent, with an equivalent of trifluoroacetic acid for one to two hours. Starting material IV, (8'hydroxy-2-(methylsulfinyl)-l'acetonaphthone) is also novel and is prepared by the addition of sodium methylsulfinylmethide bc]furan-2-one.

Among the preferred compounds of the invention having formula I there may be mentioned those .wherein R represents l to 3 carbon lower alkyl or phenyl; and R is hydrogen, chloro or 1 to 3 carbon lower alkoxy.

In all of the structures in the specification and in the claims the term alkyl and the alkyl portion of alkprepared by refluxing a compound of the formula oxy is meant to include straight and branched chain alkyl radicals containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl', butyl, n-

hexyl and the like. The term halogen encompasses fication ofprocedures described by IIMota, Life SciQ ences, 7, 465 1963) and Z. Ovary and O, Bier, Proc. SocQExptl. Biol. Med, 81, 585 (1952). Consequently, the compounds I and III of this invention are useful in the treatment of asthma hay fever and other allergicconditions. H

In addition to the above-mentioned utility, the compounds of-this invention having formulas l and III also inhibit hyperacidity in aforementioned mammals when administered orally or by injection at dosages of 10 to 100 mg/kg of body weight. For example, when 2-(methy1thio)-3(2H)-benzofuranone is tested according to the procedure described by H. Shay, et al., Gastroenterology, 5, 43 (1945), in the pylorus ligated rat, at a dose of 20 mg/kg of body weight,-irijected intraperitoneally, it caused a reduction of 49.6% in volume of gastric acid and a 28% reduction in the ion acid compared to contro1s. Thus, compounds having the formulas I and III are useful in the treatment of gastric ulcers. In order to use the'compounds of the invention having formulas I and III as described above, they may be formulated with standard pharmaceutical carriers such as lactose, mannitol, dicalcium phosphate andthe like, into dosage formssuch as tablets, capsules and the like. They can also be combined with parenterally acceptable vehicles such as polyethylene glycol, sesame oil, peanut oil or the like, for injectable dosage forms.

To further illustrate the practice of this invention the following examples are included.

EXAMPLE I scii 2-(Methylthio)-3(2H)-benzofuranone.

Z-I-Iydroxy-l-[(methylsulfinyl)acetyl] benzene 1.5 g

7-M ethoxy-2 -'(methylthio )-3(2H)-,benzofuranone.

Prepared" by the general methoddescribed in Example I, starting with 2-hydroxy-3 -methoxy-1-[(methy1- sulfinyl)acetyl]benzene. Recrystallization from absolute ethanolgives white-crystals, (89 g %),,m.p. l03105."C.

Anal. :Calcd. for C H O S: 'C, 57.13; H, 4.79; S, 15.25.

Found: C, 57.28; H, 4.97; S, 15.36.

EXAMPLE III 0 SCll 2-( Methylthio )-naphtho[2,3-b]furan-3 2H )-one.

Prepared by the general procedure described in Example I, starting with 3-hydroxy-2-[(methylsulfinyl- )acetyl]naphthalene. Recrystallization from ethanol givesyellow crystals, (1.5 g 81%), m.p. 1l8-120C.

Anal. Calcd. for C I-1 C, 67.80; H, 4.38; S,

Found: C, 67.64; H, 4.46; S, 13.94.

EXAMPLE IV Me I 2-(Methylthio)naphtho[1,8-bc]pyran-3(2H)-one.

Prepared by the general procedure described in Example l, starting with 8-hydroxy-1-[(methy1sulfiny1- )acetyl]naphthalene (1 g). Recrystallization from ethanol gives yellow-brown crystals, (600 mg 64%), m.p.

(Io wire 5-Chloro-2-(methylthio )-3(2H)-benzofuranone. 5-Ch1oro-2-hydroxy-1-[(methylsu1finy1)acetyl]benzene (6.0 g) and trifluoroacetic acid (6 g) are refluxed 0.0075m) and trifluoroacetic acid (1.5 g) are refluxed in benzene (25 ml) for one hour under nitrogen. The solvent'isrernoved' u'nder'reduced pressure to give a pale yellow-oil which crystallizes on standing. Recrystallization fromethanol gave white crystals, (0.611 .g'

45%), m.p. 81-82C.

Anal. Calcd. for C H O S: C, 59.98; H, 4.47; S,

Found: C, 60.12; H, 4.49; S, 17.78.

EXAMPLE u 0 scii OMe l-l in benzene (50 ml) for one hour under nitrogen. The

solvent is removed under reduced pressure to give a EXAMPLE V1 1-Benzoyl-2-(methylthio)-3-indolinone.

x/T SCHB H wherein X is O or NCOR wherein R is lower alkyl, phenyl or naphthyl, and Z is wherein R is hydrogen, halogen or 1 to 7 carbon lower alkoxy, which comprises reacting a compound of formula II:

CH S-CH XH II wherein X and Z are as defined above, with an equivalent amount of trifluoroacetic acid, in an inert solvent,

at reflux temperature.

2. A compound of the formula I:

X/Y SCH wherein X is O or NCOR wherein R is lower alkyl, phenyl or naphthyl, and Z is wherein R is hydrogen, halogen or 1 to 7 carbon lower alkoxy.

3. A compound according to claim 2 wherein R is l to 3 carbon lower alkyl or phenyl and R is hydrogen,

7 chloro or I to 3 carbon-lower alkoxy.

4. A compound according to claim 2 which is 2-(me- -thylthio)-3(2H )-benzofuranone.

5. A compound according to claim 2 which is 7- methoxy-2-(methylthio)-3(2H)-benzofuranone.

, 6. A compound according to claim 2 which is 2-(methylthio)-naphtho[2,3-b]-furan-3(2H)-one.

7. A compound according to claim 2 which is 5 chloro-2-( methylthio-3(2H)-benzofuranone.

8. A compound according to claim 2 which is l-benzoyl-2-(methylthio)-3-indolinone. 

1. A PROCESS FOR PREPARING A COMPOUND OF THE FORMULA I:
 2. A compound of the formula I:
 3. A compound according to claim 2 wherein R is 1 to 3 carbon lower alkyl or phenyl and R'' is hydrogen, chloro or 1 to 3 carbon-lower alkOxy.
 4. A compound according to claim 2 which is 2-(methylthio)-3(2H)-benzofuranone.
 5. A compound according to claim 2 which is 7-methoxy-2-(methylthio)-3(2H)-benzofuranone.
 6. A compound according to claim 2 which is 2-(methylthio)-naphtho(2,3-b)-furan-3(2H)-one.
 7. A compound according to claim 2 which is 5-chloro-2-(methylthio-3(2H)-benzofuranone.
 8. A compound according to claim 2 which is 1-benzoyl-2-(methylthio)-3-indolinone. 